Table 2.
Anti-angiogenic agents: profile in acute toxicity assay
| Anti-angiogenic agent | NOEC (μM) | LOEC (μM) | LC50 (μM) | Off-target effects |
|---|---|---|---|---|
| VEGF/VEGFR inhibitors | ||||
| Sunitinib | 0.5 | 1 | 1.4±0.12 | Pericardial edema at 1 μM |
| Motesanib | 0.1 | 0.5 | 1.4±0.0 | Pericardial edema at 0.5 μM |
| Pazopanib | 0.5 | 1 | 3.2±0.0 | Pericardial edema at 1 μM |
| Tivozanib | 0.01 | 0.025 | 0.045±0.0071 | Pericardial edema at 0.025 μM |
| Vandetanib | 10 | 25 | 26.0±5.29 | Pericardial edema at 25 μM |
| Vatalanib | 0.1 | 0.1 | 1.0±0.48 | Pericardial edema, yolk edema, jaw deformity at 0.1 μM, un-inflated swim bladder |
| SU5416 | 0.5 | 1 | 2.57±0.12 | Pericardial edema, yolk edema, blood pooling, shortened body axis, jaw deformity at 1 μM, un-inflated swim bladder |
| Axitinib | 0.1 | 0.5 | 1.0±0.0 | Pericardial edema at 0.5 μM |
| Cabozantinib | 0.05 | 0.1 | 0.55±0.07 | Pericardial edema at 0.1 μM |
| Multikinase inhibitors | ||||
| Sorafenib | 0.2 | 1 | 2.0±0.09 | Pericardial edema at 1 μM |
| Flavopiridol | 0.5 | 1 | 2.32±0.05 | Yolk edema, blood pooling, shortened body axis at 2 μM, widespread tissue necrosis |
| Suramin | 150 | 200 | 415.0±0.0 | Notochord deformities at 200 μM, pericardial edema |
| Regorafenib | 0.05 | 0.1 | 0.625±0.04 | Pericardial edema at 0.1 μM |
| Inhibitors of endothelial cell proliferation | ||||
| Thalidomide | 200 | 250 | 342.0±10.91 | Abnormal fin development, decreased otolith size |
| TNP-470 | 50 | 100 | 205.0±1.71 | Yolk edema at ≥100 μM |
| Combretastatin | 0.001 | 0.005 | 0.0059±0.0084 | Coagulated eggs at ≥0.01 μM |
| Erlotinib | 1 | Compound precipitation | Not reached | None up to 1 μM |
Notes: The toxicological parameters were derived from three independent biological replicates, wherein all the anti-angiogenic agents were evaluated at five different concentrations with a spacing factor of 2, and 12 embryos/concentration in each biological replicate. Bevacizumab evaluation in the toxicological study led to results too inconclusive to derive any relevant toxicological parameters.
Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; NOEC, no observed effect concentration; LOEC, lowest compound concentration that had a significant effect on 50% of the zebrafish larval population when compared with the controls; LC50, median lethal concentration that resulted in 50% mortality of the embryos over a period of 96 hours.